CA1308730C - Platinum coordination compounds - Google Patents
Platinum coordination compoundsInfo
- Publication number
- CA1308730C CA1308730C CA000520654A CA520654A CA1308730C CA 1308730 C CA1308730 C CA 1308730C CA 000520654 A CA000520654 A CA 000520654A CA 520654 A CA520654 A CA 520654A CA 1308730 C CA1308730 C CA 1308730C
- Authority
- CA
- Canada
- Prior art keywords
- platinum
- dioxolane
- aminomethyl
- compound
- bis
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 35
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 title description 4
- 229910052697 platinum Inorganic materials 0.000 title description 2
- HRGDZIGMBDGFTC-UHFFFAOYSA-N platinum(2+) Chemical compound [Pt+2] HRGDZIGMBDGFTC-UHFFFAOYSA-N 0.000 claims abstract description 14
- 238000006243 chemical reaction Methods 0.000 claims description 10
- 238000002360 preparation method Methods 0.000 claims description 7
- 239000000203 mixture Substances 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 5
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 claims description 4
- 229920000642 polymer Polymers 0.000 claims description 4
- FHIVAFMUCKRCQO-UHFFFAOYSA-N diazinon Chemical compound CCOP(=S)(OCC)OC1=CC(C)=NC(C(C)C)=N1 FHIVAFMUCKRCQO-UHFFFAOYSA-N 0.000 claims description 3
- IEVTXPMHWLBUQT-UHFFFAOYSA-N 2,2-dimethyl-1,3-dioxolane-4,5-dicarbonitrile Chemical compound CC1(C)OC(C#N)C(C#N)O1 IEVTXPMHWLBUQT-UHFFFAOYSA-N 0.000 claims description 2
- IVRMZWNICZWHMI-UHFFFAOYSA-N Azide Chemical compound [N-]=[N+]=[N-] IVRMZWNICZWHMI-UHFFFAOYSA-N 0.000 claims description 2
- CWFAVNVWAZXVOH-UHFFFAOYSA-N [2-(aminomethyl)-1,3-dioxolan-2-yl]methanamine Chemical compound NCC1(CN)OCCO1 CWFAVNVWAZXVOH-UHFFFAOYSA-N 0.000 claims description 2
- IVKNYMXGZKPFOJ-UHFFFAOYSA-N [5-(aminomethyl)-1,3-dioxolan-4-yl]methanamine Chemical compound NCC1OCOC1CN IVKNYMXGZKPFOJ-UHFFFAOYSA-N 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 125000000129 anionic group Chemical group 0.000 claims description 2
- 150000004985 diamines Chemical class 0.000 claims description 2
- 239000003085 diluting agent Substances 0.000 claims description 2
- 238000006073 displacement reaction Methods 0.000 claims description 2
- 150000004820 halides Chemical class 0.000 claims description 2
- 230000007935 neutral effect Effects 0.000 claims description 2
- 230000000269 nucleophilic effect Effects 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 125000004432 carbon atom Chemical group C* 0.000 claims 1
- 239000002552 dosage form Substances 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 claims 1
- 239000008194 pharmaceutical composition Substances 0.000 claims 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims 1
- 206010028980 Neoplasm Diseases 0.000 abstract description 5
- 201000011510 cancer Diseases 0.000 abstract description 3
- 229920005565 cyclic polymer Polymers 0.000 abstract 1
- 239000000178 monomer Substances 0.000 abstract 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 11
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 5
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- HGVNXEVNBBVJGZ-UHFFFAOYSA-N O1C2=C(N(C3=CC=CC=C13)C1=CC=C(C3=CC(C#N)=C(C#N)C=C3C3=CC=C(N4C5=CC=CC=C5OC5=C4C=CC=C5)C=C3)C=C1)C=CC=C2 Chemical compound O1C2=C(N(C3=CC=CC=C13)C1=CC=C(C3=CC(C#N)=C(C#N)C=C3C3=CC=C(N4C5=CC=CC=C5OC5=C4C=CC=C5)C=C3)C=C1)C=CC=C2 HGVNXEVNBBVJGZ-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 3
- 238000000921 elemental analysis Methods 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 229910052700 potassium Inorganic materials 0.000 description 3
- 239000011591 potassium Substances 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 239000006188 syrup Substances 0.000 description 3
- 235000020357 syrup Nutrition 0.000 description 3
- XXJGBENTLXFVFI-UHFFFAOYSA-N 1-amino-methylene Chemical compound N[CH2] XXJGBENTLXFVFI-UHFFFAOYSA-N 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 2
- MCWXGJITAZMZEV-UHFFFAOYSA-N dimethoate Chemical class CNC(=O)CSP(=S)(OC)OC MCWXGJITAZMZEV-UHFFFAOYSA-N 0.000 description 2
- YWEUIGNSBFLMFL-UHFFFAOYSA-N diphosphonate Chemical compound O=P(=O)OP(=O)=O YWEUIGNSBFLMFL-UHFFFAOYSA-N 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 2
- DLYUQMMRRRQYAE-UHFFFAOYSA-N phosphorus pentoxide Inorganic materials O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- JQWHASGSAFIOCM-UHFFFAOYSA-M sodium periodate Chemical compound [Na+].[O-]I(=O)(=O)=O JQWHASGSAFIOCM-UHFFFAOYSA-M 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- IVWWFWFVSWOTLP-YVZVNANGSA-N (3'as,4r,7'as)-2,2,2',2'-tetramethylspiro[1,3-dioxolane-4,6'-4,7a-dihydro-3ah-[1,3]dioxolo[4,5-c]pyran]-7'-one Chemical compound C([C@@H]1OC(O[C@@H]1C1=O)(C)C)O[C@]21COC(C)(C)O2 IVWWFWFVSWOTLP-YVZVNANGSA-N 0.000 description 1
- LYINTWKRUWVLBA-UHFFFAOYSA-N 2-phenyl-1,3-dioxolane Chemical compound O1CCOC1C1=CC=CC=C1 LYINTWKRUWVLBA-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- ULGZDMOVFRHVEP-RWJQBGPGSA-N Erythromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 ULGZDMOVFRHVEP-RWJQBGPGSA-N 0.000 description 1
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 1
- 238000004566 IR spectroscopy Methods 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 1
- 241000786363 Rhampholeon spectrum Species 0.000 description 1
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- CSKNSYBAZOQPLR-UHFFFAOYSA-N benzenesulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=CC=C1 CSKNSYBAZOQPLR-UHFFFAOYSA-N 0.000 description 1
- 239000001273 butane Substances 0.000 description 1
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 1
- 238000010531 catalytic reduction reaction Methods 0.000 description 1
- 239000003610 charcoal Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- DQYBDCGIPTYXML-UHFFFAOYSA-N ethoxyethane;hydrate Chemical compound O.CCOCC DQYBDCGIPTYXML-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 125000004005 formimidoyl group Chemical group [H]\N=C(/[H])* 0.000 description 1
- ZZUFCTLCJUWOSV-UHFFFAOYSA-N furosemide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(C(O)=O)=C1NCC1=CC=CO1 ZZUFCTLCJUWOSV-UHFFFAOYSA-N 0.000 description 1
- 150000004678 hydrides Chemical class 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 231100001231 less toxic Toxicity 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
- IJDNQMDRQITEOD-UHFFFAOYSA-N n-butane Chemical compound CCCC IJDNQMDRQITEOD-UHFFFAOYSA-N 0.000 description 1
- OFBQJSOFQDEBGM-UHFFFAOYSA-N n-pentane Natural products CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 1
- 229910000069 nitrogen hydride Inorganic materials 0.000 description 1
- KHIWWQKSHDUIBK-UHFFFAOYSA-M periodate Chemical compound [O-]I(=O)(=O)=O KHIWWQKSHDUIBK-UHFFFAOYSA-M 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- XOJVVFBFDXDTEG-UHFFFAOYSA-N pristane Chemical compound CC(C)CCCC(C)CCCC(C)CCCC(C)C XOJVVFBFDXDTEG-UHFFFAOYSA-N 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table
- C07F15/0006—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table compounds of the platinum group
- C07F15/0086—Platinum compounds
- C07F15/0093—Platinum compounds without a metal-carbon linkage
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
- C07D317/14—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D317/28—Radicals substituted by nitrogen atoms
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Animal Behavior & Ethology (AREA)
- General Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Materials For Photolithography (AREA)
- Catalysts (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Electrotherapy Devices (AREA)
- Mechanical Coupling Of Light Guides (AREA)
Abstract
ABSTRACT
Coordination compounds of platinum(II) with 4,5-bis(aminomethyl)-1,-3-dioxolane, intended for use in the treatment of cancer. The compounds may exist as monomers or as linear or cyclic polymers.
Coordination compounds of platinum(II) with 4,5-bis(aminomethyl)-1,-3-dioxolane, intended for use in the treatment of cancer. The compounds may exist as monomers or as linear or cyclic polymers.
Description
. l7^373n JC(MB)931 PLATINUM COORDINATION COMPOUNDS
Thls lnventlon relstes to platlnum coordination compounds for the treatment of cancer.
Since the inltial dlscovery by Rosenberg that the compount known generically as "cisplatiD (cis-dichlorodiammiDe-platinum(II)) 18 an sctive drug against certain types of cancer, there have been many attempts to provide analogous compounds which are either more active, less toxic and/or have a broader ~pectrum of activity. Various promising compounds have emerged as a :~ : resuIt, although it has remained impossible from studles of ' . . . . . .. . , . ,. - .. ... .
1 J ~, ~J ~ ~~ 0 ~tructure/activity relationships to predict with any confidence the extent to which a proposed new compound wlll show antl-tumour actlvity.
We have now found that compounds of platinum(II) with certain bi~(aminomethyl)-dioxolanes show promise as potential anti-csncer agents.
Accordingly, the present invention provides coordination compounds of platinum(II) with a 4,5-bis(aminomethyl)-1,3-dioxolane.
C~mpounts according to the lnventlon comprise the general formula ~ / t (I) 25 H2NCH2 ~ 2NH2 1 3~"`730 in which the X groups are the same or different and are selected from mono-valent and di-valent anionic moieties and neutral ~oieties such that the total charge thereof is -2, or together represent a dlvalent bidentate moiety, the R groups are the 6ame S or different and are selected from H, alkyl and aryl, and n is 1 or an integer greater than 1.
When n is 1, compounds according to the invention have the general formula H
X / \ D-'~' CN2NN2 ~ \ X (II) and when n is greater than 1, compounds according to the invent$on may be cycllc polymers or linear polymers having the general formula I J ~ O
R R C X ; C
0 / \ 0 ~ ! 0 0 \ ~ H - C - C - H
H - - C - H / \ H - C - C 11 / \ I
S H2N 2 CH2NH2 H2NCH2 CH2N~2 H2NCH2 CH2NH2 in which m is zero or an integer up to and including (n - l).
Preferably the X group~ in general formula (I), (II) or (III) are both halide, for example chlorlde. When X i8 chloride and R
16 methyl, the monomeric compound (II) may be named ci~-dlchloro~4,5-bls~aminomethyl-2,2~dimethyl-1,3-dioxolane~
platinum (II).
The b16(aminomethyl)-d$oxolane molety of compound6 according to the inventlon can exist ln enantiomeric forms (threo stereochemi6try) or as a meso-form (erythro 6tereochemistry) and the invention lnclude6 compound6 incorporating the indivitual :~ 20 stereoisomers as well as mixtures thereof.
: ::
,~
' ~ ! O
The enantiomer moieties where the R groups are methyl are as follows, in which the absolute conflguration at each chlral centre ls deslgnated uslng the Cahn-Ingold-Prelog nomenclature:-5 H3C 0 ~~ ~ / CH2 _ / C
C ¦ (4R, 5R) H3C ~ - - ~ H2 NH2 and H
H3C _/ ~ C ~ ~ CH2 ~ NH2 H3C ~o ~ CH2 ~ ' (4S,5S) The invention also lncludes a pharmaceutlcal composition compriging a compound of general formula (I) in association ~ith a pharmsceutlcally-scceptable carrier, diluent or excipient.
20Compositlons according to the inventlon are suitable for parenteral or oral administration.
:: ' Compounds according to the invention may be prepared by ; : touble nucleophilic displacement on a di-sulphonate ester of :~25 2,3-0-isopropylidene-threitol (for exsmple the ~di-methanes~lphonate or the dl- r tolueneeulphonate) vlth zlde ior , ' I J.~ ~, 7 !, to form the diazide, reduct$on to the corresponding diamine and reactlon of the latter with platlnum(II).
Such a reaction sequence is illustratet for R ~ ~ethyl by way of example in Scheme 1, for the preparation of the (4R, 5R)-compound. The starting material, the known 3,4-0-isopropylldene-D-mannitol (1), is reacted with periodate ion, and the product of glycol cleavage is reduced with æodium borohydride to afford 2,3-0-iæopropylidene-D-threitol (2).
Sulphonylation of (2) with methanesulphonyl chloride affords the di-methanesulphonate (3), which undergoes diæplacement with azide ion to yield the diazide(4). Catalytic reduction of (4) giveæ the (4R,5R~-dlamine (5), which iB reacted, generally without l~olatlon, with potassium tetrachloroplatinate, to afford (4R,5R~-(I~.
_ 7 _ 1 ` ~,73~
Scheme 1 CH 20H :H 20H
HO _ O ~
5 ~ /Me ( i ) IO4 ~ Me -- O (ii) BH4 -- O
>
(1) (2) CH 20M~ CH 2 N 3 Hc502Cl/py ~$ F3-/DMF p H201~S~ H2N3 (3) (4) O, i D ~leOU ~ R 2P t C 1 L / 1 2 ( 4R, 5R ) - ( I ) (S) ~ 3 j7 ,~
In Scheme 1, the lntermediate compound (4), 1,4-diazido-1,4-dideoxy-2,3-0-isopropylidenethreitol taS the D-enantlomer, although the L-enantiomer may be prepared by the same reaction sequence starting from the corresponting L-~annitol), is a novel compound.
Compounds according to the invention where R ~ methyl may also be prepared by reduction of 2,2-dimethyl-1,3-dioxolane-4, 5-dicarbonitrile to the bis(aminomethyl)-dioxolane and reaction of the latter with platinum(II). Such a reaction sequence is illustrated by way of example in Scheme 2 for the preparation of the 4S,5S compound. The reaction scheme starts wlth (2R,3R)-dlmethyl 2,3-0-lsopropylidenetartrste [(4R,5R~-dlmethyl 2,2-dlmethyl-1,3-dloxolane-4,5-dicarboxylate] (6) whlch is converted, by reaction with ammonia, to the dicarboxamide (7), which is dehydratet to give the dicarbonitrile (8). The latter compound is reduced to the (4S,5S)-bis(aminomethyl) compound (9), whlch is reacted wlth pota~slum tetrachloroplatinate to glve (4S,5S)-(I). The same reaction sequence, Rtarting with the enantiomer of (6), that is, (2S,3S)-dimethyl 2,3-0-isopropylldenetartrate, could equally be used for the preparation of (4R,5R)-(I).
3 ~
Scheme 2 COOMe CONH2 -O -O
~ Me NH3/H20/MeOH ~ Me O _ / Me -- > Me OOMe ONH2 (6) (7) --O _ H20H2--PhSO2Cl/py l LlAlH4 ~ Me R2PtC14 _ ______~ ~ 45,55)~(}) (8) (9) One way of determining whether the compounds as prepared exist according to geDeral formula (I), (II) or (III) may be measurement of the molecular weight.
The ~teps of the above synthetic reaction fichemes will ; nov be descrlbed by way of example.
, ',' ' 1 7 ^ ~,7 ~,r) E ~PLE l Preparation of the (4R, SR~
The starting material (1) (3,4-0-isopropylidene-D-mannitol) waS
reacted with sodium periodate and potassium borohydride as described in J. Chem. Soc., Perkin Trans. I., 1972, 275 t~ yield compound (2) in 92Z yield. Compound (2) (5.lg) was dissolved in pyridine (40ml) and cooled in ice. To this solut~on was added methanesulphonyl chloride (18ml), dropwise with stirring. The mixture vas allowed to stand at room temperature for 3 hours, after wh$ch time it was added to a solution of sodium bicarbonatè. Thls solut~on was then exttacted wlth dlchloromethane (5 x 50ml) and the combined extracts were dried (MgS04) and concentrated in vacuo. The residue obtained was recrystalllsed from ethanol to give 2,3-0-isopropylidene-1,4-di-0-methanesulphonyl-D-threltol (3), ~6.6g, 66%), m.p. 83-85~C.
Compound (3) (3g) was dissolved in N,N-dimethylformamide (100ml) and sodium azide (4.9g) was added. The mixture was heated under reflux for 3 hours. The cooled solution was diluted with dichloromethane (150ml) and filtered. The solution was then washed with water (2 x SOml), treated with charcoal, dried (~gS04) ~,1 .
, v 7~
and concentrated in vacuo to give 1,4-dla~ido-1,4-dideoxy-2,3-0-lsopropylldene-D-threltol (4), (1.3g, 65~).
Compound (4) (1.13g) was dissolved in "Analar-' methanol (50 ml) and hydrogenated over 5,. palladium on charcoal (0.2g) until thin layer chromatography showed that all starting material had been consu~ed. The suspension was filtered and the filtrate was concentrated in vacuo to give a syrup (0.613g) whose l.R.
spectrum showed no absorption at 2110cm 1 (-N3) and which was assumed to be (4R,SR)-4,5-bi6(amino~ethyl)-2,2-dlmethyl-l,3-dioxoiane (5). This material was dlssolved in water (5ml) aDd a ~olution of potasslum tetrschloroplatlnate (1.58g~ ln water (lOml) was added. The mlxture was chllled overnlght whereupon a pale orange preclpltate appeared. After centrlfuglng, the supernatant llquor was removet and the precipltate was washed successively with water, ethanol, and diethyl ether. The residue was dried over phosphorus pentoxide to glve the product.
; 20 The intermediate and final products were characterised by elemental analysis and infra-red spectroscopy.
~lemental analysis:
C H ~ Cl Required: 19.76 3.53 6.59 16.71 Found: 19.61 3.72 6.58 16.93 * is a Trademark .
1 7 ~ ~ 7 ~ ~
~J
Preparation of (4S, SS)-(I):-The starting material (6) [(4R,5R-)-dimethyl-2,2-dimeth~l-1,3-dioxalane-4,5-dicarboxylate] was reacted in methanol with concentrated aqueous ammonia to give the diamide (7), which was reacted with benzenesulphonyl chloride in dry pyridine to give the dicarbonitrile (8), according to the method disclosed in J. Chem.
Soc., Perkin Trans. I., 1985, 795~ The dicarbonitrile (lg) WaS
dissolved in dry diethyl ether (lOOml) and added to a suspension of lithium alumlniu~ hydride (1.3g) in dry diethyl ether (40ml).
The suspenslon was then fitirred for 4 hours at roo~ temperature.
Water (0.5ml) was then added to the reactlon mi~ture followed at 5 mlnute lntervals by a 15Z sodium hydro~ide solution ~0.6ml) and water (1.9ml). The solution was then filtered and the flltrate was dried (~gSO4) and concentrated in vacuo to give a syrup which was assumçd to be (4S,SS)-4,5-bis(aminomethyl)-2,2-dimethyl-1,3-dioxolane (0.27g) (9). This syrup was dissolved in water and asolution of potassium tetrachloroplatinate (0.7g) in water (lOml) was added with stirring. After 15 minutes. at room temperarure a pale orange precipitate began to form. The suspension was stored overnight at 0C and, after centrlfuging, the supernatant liguor ~' .
1 J ~ ) 7 _J C) was re ved and the preclpltate was washed successively with water, ethanol, and dlethyl ether. The pale orange powder was then dried over phosphorus pentoxide to give the product.
The intermediate and final products were characterised by elemental analysis and lnfra-red spectroscopy.
Elemental analysis C ~ N Cl Required: 19.76 3.53 6.59 16.71 Yound: 19.39 3.72 6.41 16.92 Co~pounds accorting to the lnventlon were ~creened for anti-tumour actlvity agalnst AD3/PC6 tumour implanted lnto female Balb C~ mice, compared with a chemically similar compount not accorting to the invention. Compounds were administered both parenterally (IP) ant orally (PO). Results were as follows :-i 1 3~730 _ COMPOUND Route LD50 EDgo TI
S __ _ cl6-tichloro[(4R,5R)-4,5-bi6(aminomethyl)- IP 35 1.6 22.6 2,2-dimethyl-1,3-tioxolane]platinum(II) PO 1100 9 122 cis-dichloro[(4S,5S)-4,5-bi6(aminomethyl)- IP 35 1.46 23.9 2,2-dimethyl-1,3-dio~olane]platinum(II) PO 1130 26 43.5 cis-dichloro[(4S,5S)-4,5-bis(aminomethyl)- IP >800 30 >26 2-phenyl-1,3-dioxolane]platinum (II) PO >1600 ~1600 >1 ci6-di~romo[4,5-bis(aminomethyl)-2,2-dimethyl-1,3-dio~olane]platinum (II) IP 21 4 5.2 (racemic mixture) cis-dichloro[2,3-dihydroxy-1,2-diamino IP>400 380 >1 butane)-platinum (II) ~comparative example) PO>800 _ _
Thls lnventlon relstes to platlnum coordination compounds for the treatment of cancer.
Since the inltial dlscovery by Rosenberg that the compount known generically as "cisplatiD (cis-dichlorodiammiDe-platinum(II)) 18 an sctive drug against certain types of cancer, there have been many attempts to provide analogous compounds which are either more active, less toxic and/or have a broader ~pectrum of activity. Various promising compounds have emerged as a :~ : resuIt, although it has remained impossible from studles of ' . . . . . .. . , . ,. - .. ... .
1 J ~, ~J ~ ~~ 0 ~tructure/activity relationships to predict with any confidence the extent to which a proposed new compound wlll show antl-tumour actlvity.
We have now found that compounds of platinum(II) with certain bi~(aminomethyl)-dioxolanes show promise as potential anti-csncer agents.
Accordingly, the present invention provides coordination compounds of platinum(II) with a 4,5-bis(aminomethyl)-1,3-dioxolane.
C~mpounts according to the lnventlon comprise the general formula ~ / t (I) 25 H2NCH2 ~ 2NH2 1 3~"`730 in which the X groups are the same or different and are selected from mono-valent and di-valent anionic moieties and neutral ~oieties such that the total charge thereof is -2, or together represent a dlvalent bidentate moiety, the R groups are the 6ame S or different and are selected from H, alkyl and aryl, and n is 1 or an integer greater than 1.
When n is 1, compounds according to the invention have the general formula H
X / \ D-'~' CN2NN2 ~ \ X (II) and when n is greater than 1, compounds according to the invent$on may be cycllc polymers or linear polymers having the general formula I J ~ O
R R C X ; C
0 / \ 0 ~ ! 0 0 \ ~ H - C - C - H
H - - C - H / \ H - C - C 11 / \ I
S H2N 2 CH2NH2 H2NCH2 CH2N~2 H2NCH2 CH2NH2 in which m is zero or an integer up to and including (n - l).
Preferably the X group~ in general formula (I), (II) or (III) are both halide, for example chlorlde. When X i8 chloride and R
16 methyl, the monomeric compound (II) may be named ci~-dlchloro~4,5-bls~aminomethyl-2,2~dimethyl-1,3-dioxolane~
platinum (II).
The b16(aminomethyl)-d$oxolane molety of compound6 according to the inventlon can exist ln enantiomeric forms (threo stereochemi6try) or as a meso-form (erythro 6tereochemistry) and the invention lnclude6 compound6 incorporating the indivitual :~ 20 stereoisomers as well as mixtures thereof.
: ::
,~
' ~ ! O
The enantiomer moieties where the R groups are methyl are as follows, in which the absolute conflguration at each chlral centre ls deslgnated uslng the Cahn-Ingold-Prelog nomenclature:-5 H3C 0 ~~ ~ / CH2 _ / C
C ¦ (4R, 5R) H3C ~ - - ~ H2 NH2 and H
H3C _/ ~ C ~ ~ CH2 ~ NH2 H3C ~o ~ CH2 ~ ' (4S,5S) The invention also lncludes a pharmaceutlcal composition compriging a compound of general formula (I) in association ~ith a pharmsceutlcally-scceptable carrier, diluent or excipient.
20Compositlons according to the inventlon are suitable for parenteral or oral administration.
:: ' Compounds according to the invention may be prepared by ; : touble nucleophilic displacement on a di-sulphonate ester of :~25 2,3-0-isopropylidene-threitol (for exsmple the ~di-methanes~lphonate or the dl- r tolueneeulphonate) vlth zlde ior , ' I J.~ ~, 7 !, to form the diazide, reduct$on to the corresponding diamine and reactlon of the latter with platlnum(II).
Such a reaction sequence is illustratet for R ~ ~ethyl by way of example in Scheme 1, for the preparation of the (4R, 5R)-compound. The starting material, the known 3,4-0-isopropylldene-D-mannitol (1), is reacted with periodate ion, and the product of glycol cleavage is reduced with æodium borohydride to afford 2,3-0-iæopropylidene-D-threitol (2).
Sulphonylation of (2) with methanesulphonyl chloride affords the di-methanesulphonate (3), which undergoes diæplacement with azide ion to yield the diazide(4). Catalytic reduction of (4) giveæ the (4R,5R~-dlamine (5), which iB reacted, generally without l~olatlon, with potassium tetrachloroplatinate, to afford (4R,5R~-(I~.
_ 7 _ 1 ` ~,73~
Scheme 1 CH 20H :H 20H
HO _ O ~
5 ~ /Me ( i ) IO4 ~ Me -- O (ii) BH4 -- O
>
(1) (2) CH 20M~ CH 2 N 3 Hc502Cl/py ~$ F3-/DMF p H201~S~ H2N3 (3) (4) O, i D ~leOU ~ R 2P t C 1 L / 1 2 ( 4R, 5R ) - ( I ) (S) ~ 3 j7 ,~
In Scheme 1, the lntermediate compound (4), 1,4-diazido-1,4-dideoxy-2,3-0-isopropylidenethreitol taS the D-enantlomer, although the L-enantiomer may be prepared by the same reaction sequence starting from the corresponting L-~annitol), is a novel compound.
Compounds according to the invention where R ~ methyl may also be prepared by reduction of 2,2-dimethyl-1,3-dioxolane-4, 5-dicarbonitrile to the bis(aminomethyl)-dioxolane and reaction of the latter with platinum(II). Such a reaction sequence is illustrated by way of example in Scheme 2 for the preparation of the 4S,5S compound. The reaction scheme starts wlth (2R,3R)-dlmethyl 2,3-0-lsopropylidenetartrste [(4R,5R~-dlmethyl 2,2-dlmethyl-1,3-dloxolane-4,5-dicarboxylate] (6) whlch is converted, by reaction with ammonia, to the dicarboxamide (7), which is dehydratet to give the dicarbonitrile (8). The latter compound is reduced to the (4S,5S)-bis(aminomethyl) compound (9), whlch is reacted wlth pota~slum tetrachloroplatinate to glve (4S,5S)-(I). The same reaction sequence, Rtarting with the enantiomer of (6), that is, (2S,3S)-dimethyl 2,3-0-isopropylldenetartrate, could equally be used for the preparation of (4R,5R)-(I).
3 ~
Scheme 2 COOMe CONH2 -O -O
~ Me NH3/H20/MeOH ~ Me O _ / Me -- > Me OOMe ONH2 (6) (7) --O _ H20H2--PhSO2Cl/py l LlAlH4 ~ Me R2PtC14 _ ______~ ~ 45,55)~(}) (8) (9) One way of determining whether the compounds as prepared exist according to geDeral formula (I), (II) or (III) may be measurement of the molecular weight.
The ~teps of the above synthetic reaction fichemes will ; nov be descrlbed by way of example.
, ',' ' 1 7 ^ ~,7 ~,r) E ~PLE l Preparation of the (4R, SR~
The starting material (1) (3,4-0-isopropylidene-D-mannitol) waS
reacted with sodium periodate and potassium borohydride as described in J. Chem. Soc., Perkin Trans. I., 1972, 275 t~ yield compound (2) in 92Z yield. Compound (2) (5.lg) was dissolved in pyridine (40ml) and cooled in ice. To this solut~on was added methanesulphonyl chloride (18ml), dropwise with stirring. The mixture vas allowed to stand at room temperature for 3 hours, after wh$ch time it was added to a solution of sodium bicarbonatè. Thls solut~on was then exttacted wlth dlchloromethane (5 x 50ml) and the combined extracts were dried (MgS04) and concentrated in vacuo. The residue obtained was recrystalllsed from ethanol to give 2,3-0-isopropylidene-1,4-di-0-methanesulphonyl-D-threltol (3), ~6.6g, 66%), m.p. 83-85~C.
Compound (3) (3g) was dissolved in N,N-dimethylformamide (100ml) and sodium azide (4.9g) was added. The mixture was heated under reflux for 3 hours. The cooled solution was diluted with dichloromethane (150ml) and filtered. The solution was then washed with water (2 x SOml), treated with charcoal, dried (~gS04) ~,1 .
, v 7~
and concentrated in vacuo to give 1,4-dla~ido-1,4-dideoxy-2,3-0-lsopropylldene-D-threltol (4), (1.3g, 65~).
Compound (4) (1.13g) was dissolved in "Analar-' methanol (50 ml) and hydrogenated over 5,. palladium on charcoal (0.2g) until thin layer chromatography showed that all starting material had been consu~ed. The suspension was filtered and the filtrate was concentrated in vacuo to give a syrup (0.613g) whose l.R.
spectrum showed no absorption at 2110cm 1 (-N3) and which was assumed to be (4R,SR)-4,5-bi6(amino~ethyl)-2,2-dlmethyl-l,3-dioxoiane (5). This material was dlssolved in water (5ml) aDd a ~olution of potasslum tetrschloroplatlnate (1.58g~ ln water (lOml) was added. The mlxture was chllled overnlght whereupon a pale orange preclpltate appeared. After centrlfuglng, the supernatant llquor was removet and the precipltate was washed successively with water, ethanol, and diethyl ether. The residue was dried over phosphorus pentoxide to glve the product.
; 20 The intermediate and final products were characterised by elemental analysis and infra-red spectroscopy.
~lemental analysis:
C H ~ Cl Required: 19.76 3.53 6.59 16.71 Found: 19.61 3.72 6.58 16.93 * is a Trademark .
1 7 ~ ~ 7 ~ ~
~J
Preparation of (4S, SS)-(I):-The starting material (6) [(4R,5R-)-dimethyl-2,2-dimeth~l-1,3-dioxalane-4,5-dicarboxylate] was reacted in methanol with concentrated aqueous ammonia to give the diamide (7), which was reacted with benzenesulphonyl chloride in dry pyridine to give the dicarbonitrile (8), according to the method disclosed in J. Chem.
Soc., Perkin Trans. I., 1985, 795~ The dicarbonitrile (lg) WaS
dissolved in dry diethyl ether (lOOml) and added to a suspension of lithium alumlniu~ hydride (1.3g) in dry diethyl ether (40ml).
The suspenslon was then fitirred for 4 hours at roo~ temperature.
Water (0.5ml) was then added to the reactlon mi~ture followed at 5 mlnute lntervals by a 15Z sodium hydro~ide solution ~0.6ml) and water (1.9ml). The solution was then filtered and the flltrate was dried (~gSO4) and concentrated in vacuo to give a syrup which was assumçd to be (4S,SS)-4,5-bis(aminomethyl)-2,2-dimethyl-1,3-dioxolane (0.27g) (9). This syrup was dissolved in water and asolution of potassium tetrachloroplatinate (0.7g) in water (lOml) was added with stirring. After 15 minutes. at room temperarure a pale orange precipitate began to form. The suspension was stored overnight at 0C and, after centrlfuging, the supernatant liguor ~' .
1 J ~ ) 7 _J C) was re ved and the preclpltate was washed successively with water, ethanol, and dlethyl ether. The pale orange powder was then dried over phosphorus pentoxide to give the product.
The intermediate and final products were characterised by elemental analysis and lnfra-red spectroscopy.
Elemental analysis C ~ N Cl Required: 19.76 3.53 6.59 16.71 Yound: 19.39 3.72 6.41 16.92 Co~pounds accorting to the lnventlon were ~creened for anti-tumour actlvity agalnst AD3/PC6 tumour implanted lnto female Balb C~ mice, compared with a chemically similar compount not accorting to the invention. Compounds were administered both parenterally (IP) ant orally (PO). Results were as follows :-i 1 3~730 _ COMPOUND Route LD50 EDgo TI
S __ _ cl6-tichloro[(4R,5R)-4,5-bi6(aminomethyl)- IP 35 1.6 22.6 2,2-dimethyl-1,3-tioxolane]platinum(II) PO 1100 9 122 cis-dichloro[(4S,5S)-4,5-bi6(aminomethyl)- IP 35 1.46 23.9 2,2-dimethyl-1,3-dio~olane]platinum(II) PO 1130 26 43.5 cis-dichloro[(4S,5S)-4,5-bis(aminomethyl)- IP >800 30 >26 2-phenyl-1,3-dioxolane]platinum (II) PO >1600 ~1600 >1 ci6-di~romo[4,5-bis(aminomethyl)-2,2-dimethyl-1,3-dio~olane]platinum (II) IP 21 4 5.2 (racemic mixture) cis-dichloro[2,3-dihydroxy-1,2-diamino IP>400 380 >1 butane)-platinum (II) ~comparative example) PO>800 _ _
Claims (8)
1. A coordination compound of platinum(II) with a 4,5-bis(aminomethyl)-1,3-dioxolane having the formula in which the X groups are the same or different and are selected from mono-valent and di-valent anionic moieties and neutral moieties such that the total charge thereof is -2, or together represent a divalent bidentate moiety, the R groups are the same or different and are selected from H, alkyl having 1 to 4 carbon atoms and phenyl, and n is 1 or an integer greater than 1.
2. A compound according to claim 1 in which the X groups are both halide.
3. The compound cis-dichloro[(4R,5R)-4,5-bis-(aminomethyl) -2,2-dimethyl-1,3-dioxolane] platinum(II), existing per se or as a polymer thereof.
4. The compound cis-dichloro[(4S-5S)-4,5-bis(aminomethyl) -2,2-dimethyl-1,3-dioxolane] platinum(II), existing per se or as a polymer thereof.
5. A pharmaceutical composition comprising a compound according to claim 1 in association with a pharmaceutically acceptable carrier, diluent or excipient.
6. A composition according to claim 5 in unit dosage form.
7. A method for the preparation of a compound according to claim 1, the method comprising the steps of double nucleophilic displacement on a di-sulphonate ester of 2,3-0-isopropylidenethreitol by azide ion to form the diazide, reduction to the corresponding diamine and reaction with platinum(II).
8. A method for the preparation of a compound according to claim 1, the method comprising the steps of reduction of 2,2-dimethyl-1,3-dioxolane-4,5-dicarbonitrile to the bis(aminomethyl)dioxolane and reaction with platinum(II).
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB8525689 | 1985-10-18 | ||
| GB858525689A GB8525689D0 (en) | 1985-10-18 | 1985-10-18 | Platinum coordination compounds |
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| Publication Number | Publication Date |
|---|---|
| CA1308730C true CA1308730C (en) | 1992-10-13 |
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ID=10586856
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|---|---|---|---|
| CA000520654A Expired - Lifetime CA1308730C (en) | 1985-10-18 | 1986-10-16 | Platinum coordination compounds |
Country Status (9)
| Country | Link |
|---|---|
| US (1) | US4783452A (en) |
| EP (1) | EP0222522B1 (en) |
| JP (1) | JPS62174092A (en) |
| AT (1) | ATE51001T1 (en) |
| CA (1) | CA1308730C (en) |
| DE (1) | DE3669513D1 (en) |
| ES (1) | ES2013695B3 (en) |
| GB (1) | GB8525689D0 (en) |
| GR (1) | GR3001012T3 (en) |
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| US4870070A (en) * | 1987-08-10 | 1989-09-26 | American Cyanamid Company | Water soluble platinum complexes of novel malonate derivatives |
| US5243057A (en) * | 1989-03-07 | 1993-09-07 | Aerojet-General Corporation | Energetic azidomethyl-substituted 1,3-dioxolanes |
| CA2046313C (en) * | 1989-12-12 | 1999-09-07 | Go Hata | Platinum (ii) complex and agent for treating malignant tumor |
| AU654990B2 (en) * | 1991-03-23 | 1994-12-01 | Sunkyong Industries Ltd. | Novel platinum(II) complex and processes for preparing the same |
| AU775373B2 (en) | 1999-10-01 | 2004-07-29 | Immunogen, Inc. | Compositions and methods for treating cancer using immunoconjugates and chemotherapeutic agents |
| CN101245083B (en) * | 2008-03-18 | 2012-11-21 | 南京工业大学 | Platinum complex containing 1, 3-dioxolane structure and synthesis method and application thereof |
| RU2668203C1 (en) * | 2017-12-18 | 2018-09-26 | Юрий Федорович Тканко | Operator's seats earthquake-proof (options) |
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| NL8101026A (en) * | 1981-03-03 | 1982-10-01 | Tno | PLATINADIAMINE COMPLEXES, A METHOD FOR PREPARING THE SAME, A METHOD FOR PREPARING A MEDICINAL PRODUCT USING SUCH PLATINADIAMINE COMPLEX FOR THE TREATMENT OF CANCER AND CONTAINED IN SUCH FORM. |
| US4500465A (en) * | 1982-06-28 | 1985-02-19 | Engelhard Corporation | Solubilized platinum (II) complexes |
-
1985
- 1985-10-18 GB GB858525689A patent/GB8525689D0/en active Pending
-
1986
- 1986-10-16 CA CA000520654A patent/CA1308730C/en not_active Expired - Lifetime
- 1986-10-17 DE DE8686308085T patent/DE3669513D1/en not_active Expired - Lifetime
- 1986-10-17 AT AT86308085T patent/ATE51001T1/en not_active IP Right Cessation
- 1986-10-17 ES ES86308085T patent/ES2013695B3/en not_active Expired - Lifetime
- 1986-10-17 EP EP86308085A patent/EP0222522B1/en not_active Expired - Lifetime
- 1986-10-18 JP JP61246506A patent/JPS62174092A/en active Pending
- 1986-10-20 US US06/920,541 patent/US4783452A/en not_active Expired - Fee Related
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| Publication number | Publication date |
|---|---|
| ES2013695A4 (en) | 1990-06-01 |
| EP0222522A3 (en) | 1987-08-05 |
| EP0222522B1 (en) | 1990-03-14 |
| GB8525689D0 (en) | 1985-11-20 |
| US4783452A (en) | 1988-11-08 |
| GR3001012T3 (en) | 1991-12-30 |
| ES2013695B3 (en) | 1990-07-01 |
| JPS62174092A (en) | 1987-07-30 |
| EP0222522A2 (en) | 1987-05-20 |
| DE3669513D1 (en) | 1990-04-19 |
| ATE51001T1 (en) | 1990-03-15 |
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